The present invention relates to methods for treating leukemia, and more particularly, to the use of nucleoside analogues as an effective treatment for acute or chronic myelogenous leukemia.
Leukemia is a malignant cancer of the bone marrow and blood. It is characterized by the uncontrolled growth of blood cells. The common types of leukemia are divided into four categories: acute or chronic myelogenous, involving the myeloid elements of the bone marrow (white cells, red cells, megakaryocytes) and acute or chronic lymphocytic, involving the cells of the lymphoid lineage.
Acute leukemia is a rapidly progressing disease that results in the massive accumulation of immature, functionless cells (blasts) in the marrow and blood. The marrow often can no longer produce enough normal red and white blood cells and platelets. Anemia, a deficiency of red cells, develops in virtually all leukemia patients. The lack of normal white cells impairs the body""s ability to fight infections. A shortage of platelets results in bruising and easy bleeding. In contrast, chronic leukemia progresses more slowly and leads to unregulated proliferation and hence marked overexpansion of a spectrum of mature (differentiated) cells. In general, acute leukemia, unlike the chronic form, is potentially curable by elimination of the neoplastic clone.
Treatment of leukemia is very complex and depends upon the type of leukemia. Tremendous clinical variability among remissions is also observed in leukemic patients, even those that occur after one course of therapy. Patients who are resistant to therapy have very short survival times, regardless of when the resistance occurs.
Standard treatment for leukemia usually involves chemotherapy and/or bone marrow transplantation and/or radiation therapy. The two major types of bone marrow transplants are autologus (uses the patient""s own marrow) and allogeneic (uses marrow from a compatible donor). Radiation therapy, which involves the use of high-energy rays, and chemotherapy are usually given before bone marrow transplantation to kill all leukemic cells. In the cure for CML, bone marrow transplantation can be clearly curative. However, only 30% to 40% of patients with CML have an appropriate donor. Beyond that, the mortality from the procedure ranges from 20% to 30%, depending on the age of the recipient. Finally, this procedure is quite expensive.
Chemotherapy in leukemia may involve a combination of two or more anti-cancer drugs. Approximately 40 different drugs are now being used in the treatment of leukemia, either alone or in combination. Some common combinations include cytarabine with either doxorubicin or daunorubicin or mitoxantrone or thioguanine, mercaptopurine with methotrexate, mitroxantrone with etoposide, asparaginase with vincristine, daunorubicin and prednisone, cyclophosphamide with vincristine, cytarabine and prednisone, cyclophosphamide with vincristine and prednisone, daunorubicin with cytarabine and thioguanine and daunorubicin with vincristine and prednisone.
Other treatments for leukemia also include the reversal of multidrug resistance, involving the use of agents which decrease the mechanisms allowing the malignant cells to escape the damaging effects of the chemotherapeutic agent (and leads to refractoriness or relapses); and biological therapy, involving the use of substances known as biological response modifiers (BRMs). These substances are normally produced in small amounts as part of the body""s natural response to cancer or other diseases. Types of BRMs include monoclonal antibodies, in which toxins are attached to antibodies that react with the complementary antigen carried by the malignant cells; and cytokines (e.g. interferons, interleukins, colony-stimulating factors CSFs) which are naturally occuring chemicals that stimulate blood cell production and help restore blood cell counts more rapidly after treatment. Examples of these drugs include multidrug resistance reversing agent PSC 833, the monoclonal antibody Rituxan and the following cytokines: Erythropoetin and Epoetin, which stimulate the production of red cells; G-CSF, GM-CSF, filgrastim, and Sargramostim which stimulate the production of white cells; and thrombopoietin, which stimulate the production of platelets.
Many nucleoside analogues have been found to possess anticancer activity. Cytarabine, Fludarabine, Gemcitabine and Cladribine are some examples of nucleoside analogues which are currently important drugs in the treatment of leukemia. xcex2-L-OddC ((xe2x88x92)-xcex2-L-Dioxolane-Cytidine, Troxatyl(trademark), from Shire BioChem Inc.) is also a nucleoside analogue which was first described as an antiviral agent by Belleau et al. (EP 337713) and was shown to have potent antitumor activity (K. L. Grove et al., Cancer Res., 55(14), 3008-11, 1995; K. L. Grove et al., Cancer Res., 56(18), 4187-4191, 1996, K. L. Grove et al., Nucleosides Nucleotides, 16:1229-33, 1997; S. A Kadhim et al., Can. Cancer Res., 57(21), 4803-10, 1997). In clinical studies, xcex2-L-OddC has been reported to have significant activity in patients with advanced leukemia (Giles et al., J. Clin. Oncology, Vol 19, No 3, 2001).
More recently, STI-571 (Gleevec(trademark), imatinib mesylate, from Novartis Pharmaceuticals Corp.) a Bcr-Abl tyrosine kinase inhibitor has shown significant antileukemic activity and specifically in chronic myeologenous leukemia. STI-571 has become a promising therapy in the group of patients targeting Bcr-Abl tyrosine kinase inhibition. However, despite significant hematologic and cytogenic responses, resistance occurs particularly in the advanced phases of chronic myelogenous leukemia. Therefore, there is a great need for the further development of agents for the treatment of leukemia patients who have been previously treated with a Bcr-Abl tyrosine kinase inhibitor and have become resistant to the Bcr-Abl tyrosine kinase inhibitor.
The present invention provides a novel method for treating leukemia in a host comprising administering to a patient that has been previously treated with a Bcr-Abl tyrosine kinase inhibitor a therapeutically effective amount of a compound having the formula (1): 
wherein B is cytosine or 5-fluorocytosine and R is selected from H, monophosphate, diphosphate, triphosphate, carbonyl substituted with a C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, and 
wherein each Rc is independently selected from the group comprising H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and an hydroxy protecting group.
In another embodiment, there is provided a method for treating leukemia in a host comprising administering to a patient that has been previously treated with with a Bcr-Abl tyrosine kinase inhibitor and who has had no previous chemotherapy treatment a therapeutically effective amount of a compound of formula (I), as defined above.
In another embodiment, there is provided a method for treating leukemia in a host comprising administering to a patient that has been previously treated with a Bcr-Abl tyrosine kinase inhibitor a therapeutically effective amount of a compound according to formula (I), as defined above.
In another embodiment, there is provided a method for treating leukemia in a host comprising administering to a patient that has been previously treated with a Bcr-Abl tyrosine kinase inhibitor and has become resistant to the Bcr-Abl tyrosine kinase inhibitor treatment, a therapeutically effective amount of a compound according to formula (I), as defined above.
In another embodiment, there is provided a method for treating leukemia in a host comprising administering to a patient that has been previously treated with a Bcr-Abl tyrosine kinase inhibitor a therapeutically effective amount of a compound according to formula (I), as defined above, and at least one further therapeutic agent selected from the group comprising nucleoside analogues; chemotherapeutic agents; multidrug resistance reversing agents; and biological response modifiers.
In another embodiment, there is provided a pharmaceutical composition for treating leukemia in a patient that has been previously treated with a Bcr-Abl tyrosine kinase inhibitor comprising at least one compound according to formula (I), as defined above, and at least one further therapeutic agent selected from the group comprising nucleoside analogues; chemotherapeutic agents; multidrug resistance reversing agents; and biological response modifiers.
Still another embodiment, there is provided a pharmaceutical composition for treating leukemia in a patient that has been previously treated with a Bcr-Abl tyrosine kinase inhibitor comprising at least one compound according to formula (I), as defined above, together with at least one pharmaceutically acceptable carrier or excipient.
In another embodiment of the invention is the use of a compound according to formula (I), as defined above, for the manufacture of a medicament for treating leukemia in a patient that has been previously treated with a Bcr-Abl tyrosine kinase inhibitor.